Teneurins: a novel family of neuronal cell surface proteins in vertebrates, homologous to the Drosophila pair-rule gene product Ten-m

We have characterized chicken teneurin-1 and teneurin-2, two homologues of the Drosophila pair-rule gene product Ten-m and Drosophila Ten-a. The high degree of conservation between the vertebrate and invertebrate proteins suggests that these belong to a novel family. We propose to name the vertebrate members of this family teneurins, because of their predominant expression in the nervous system. The expression of teneurin-1 and -2 was investigated by in situ hybridization. We show that teneurin-1 and -2 are expressed by distinct populations of neurons during the time of axonal growth. The most prominent site of expression of chicken teneurins is the developing visual system. Recombinant teneurin-2 was expressed to assay its molecular and functional properties. We show that it is a type II transmembrane protein, which can be released from the cell surface by proteolytic cleavage at a furin site. The expression of teneurin-2 in neuronal cells led to a significant increase in the number of filopodia and to the formation of enlarged growth cones. The expression pattern of teneurins in the developing nervous system and the ability of teneurin-2 to reorganize the cellular morphology indicate that these proteins may have an important function in the formation of neuronal connections.     

Latrophilins Function as Heterophilic Cell-adhesion Molecules by Binding to Teneurins: REGULATION BY ALTERNATIVE SPLICING*

Latrophilin-1, -2, and -3 are adhesion-type G protein-coupled receptors that are auxiliary α-latrotoxin receptors, suggesting that they may have a synaptic function. Using pulldowns, we here identify teneurins, type II transmembrane proteins that are also candidate synaptic cell-adhesion molecules, as interactors for the lectin-like domain of latrophilins. We show that teneurin binds to latrophilins with nanomolar affinity and that this binding mediates cell adhesion, consistent with a role of teneurin binding to latrophilins in trans-synaptic interactions. All latrophilins are subject to alternative splicing at an N-terminal site; in latrophilin-1, this alternative splicing modulates teneurin binding but has no effect on binding of latrophilin-1 to another ligand, FLRT3. Addition to cultured neurons of soluble teneurin-binding fragments of latrophilin-1 decreased synapse density, suggesting that latrophilin binding to teneurin may directly or indirectly influence synapse formation and/or maintenance. These observations are potentially intriguing in view of the proposed role for Drosophila teneurins in determining synapse specificity. However, teneurins in Drosophila were suggested to act as homophilic cell-adhesion molecules, whereas our findings suggest a heterophilic interaction mechanism. Thus, we tested whether mammalian teneurins also are homophilic cell-adhesion molecules, in addition to binding to latrophilins as heterophilic cell-adhesion molecules. Strikingly, we find that although teneurins bind to each other in solution, homophilic teneurin-teneurin binding is unable to support stable cell adhesion, different from heterophilic teneurin-latrophilin binding. Thus, mammalian teneurins act as heterophilic cell-adhesion molecules that may be involved in trans-neuronal interaction processes such as synapse formation or maintenance.